We have recently identified a novel sialoglycoprotein present in human blood and body fluids. This protein has a molecular mass of 120 kDa (sgpl2O) and has a single chain structure. Like the second component of complement (C2), this protein binds to activated C4b of the classical complement pathway (CCP) and can be recovered from Sepharose linked C4b as part of an isolation and purification scheme. The sgpl2O-A isolated by this technique has been shown to regulate the assembly of the CCP C3 and C5 convertases as demonstrated by hemolytic site inhibition in a specific and dose dependent fashion. Use of radiolabeled sgpl2O-A showed its specific binding to C4b bound to antibody, sensitized sheep erythrocytes (EAC4b). Binding was both dose responsive and saturable showing specificity for C4b. Sgpl2O-A binding was inhibitable by both cold sgpl2O and C2. Preliminary data suggest that sgpl2O-l, the predominant form of the protein which does not bind to Sepharose bound C4b, binds minimally to EAC4b and that much larger amounts of sgpl2O-l are required for inhibition of the CCP, if inhibition occurs at all. As earlier reported, sgpl2O fragments possess both vasodilation and contractile capacity as demonstrated in separate guinea pig models. Sgpl2O fragmentation was assessed in the plasma of individuals with the swelling disorder hereditary angioedema (HAE). No associated fragmentation of sgpl2O was evidenced in individuals experiencing severe, active swelling. However, sgpl2O was cleaved into the characteristic fragments in all persons with inflammatory joint disease, but not in individuals with noninflammatory, joint disease.